Protonation diastereoselective

The rate of epimerization of an a-stereogenic centre within a carbonyl-containing compound with several stereogenic centres depends on the acidity of the enolizable proton. Diastereoselectivity depends on kinetic and/or thermodynamic effects (reagent and substrate control)... 

When a solution of 25 in a 1 1 mixture of methanol and methylene chloride is exposed to periodic acid, the dithiane group is cleaved oxidatively to give, after treatment of the crude product with camphorsulfonic acid (CSA) in methanol, bisacetal 12 as a 2 1 mixture of C-12 anomers in a yield of 80% (Scheme 3). Although the conversion of 12 into 10 could be carried out on the mixture of anomers, it was found to be more convenient to carry each isomer forward separately. When 12 is treated with lithium diethylamide, the methine hydrogen adjacent to the lactone carbonyl is removed as a proton to give an enolate which is then oxidized in a completely diastereoselective fashion with Davis s oxaziridine18 to afford 11. 

The Lewis acid of choice for most of the cyclization reactions is ethylaluminum dichloride, because of its exceptional properties it is a mild Lewis acid, and, as an organometallic compound, can serve as a proton sponge , and thereby inhibit competitive protodesilyla-tion37. The desired precursors reacted smoothly with 1.1 equivalents of ethylaluminum dichloride in toluene or dichloromethane at low temperature to generate diastereoselectively the desired spiro[4.5]decanones38. 

A diastereoselective route to d.v-2,3-disubstituted cyclohexanones is based on the kinetically controlled protonation of the enolate obtained via the addition of an arylacetonitrile to 2-sub-stituted 2-cycloalkenones in THF or in THF/HMPA mixtures at — 70-0 °C 299,30°, see also refs 301, 302 and 403. 

The initial nitronate anion intermediates formed from the addition of trimethylaluminum to nitroalkenes having a /i-phenylthio substituent, however, undergo a highly diastereoselective protonation to give awn -products19. 

While a different explanation for the diastereoselection in these protonation reactions has been proposed, the stereochemical sense of protonation can be rationalized as arising from protonation of the chelated intermediate from the least hindered diastereotopic face of the nitronate anion (i.e. anti to the /i-methyl group)20-21. 

The cycloaddition of glyoxylic acid with cyclopentadiene in water at pH 6 and 60 °C is slow and occurs with low yield and low diastereoselectivity [18] (Scheme 6.17). Proton (pH = 0.9) [18], copper salts [27] and Bi(OTf)3 [28] accelerate the reaction and increase the diastereoselectivity. The lactones 28 and 29 originate from endo and exo cycloadducts 27, respectively. The proposed rearrangement is depicted in Scheme 6.17 for the major endo adduct 30. A competitive ene reaction that originates 28 and 29 cannot be excluded [28]. 

Protic solvents such as i-PrOH and t-BuOH favor the diastereoselectivity of the reaction of 3-hydroxy-2-pyrone with acrylates [49b]. Further examples of proton-promoted Diels-Alder reactions are reported in Section 4.8. 

Rovis and co-workers further extended the scope of the reaction to the enantio-and diastereoselective cyclisation of a,P-disubstituted Michael acceptors 137. The high diastereoselectivity of the process relies on selective protonation of the resnltant enolate after conjugate addition. It was found that HMDS (formed dnring deprotonation of the triazolium salt pre-catalyst) was detrimental to the... 

The above-mentioned results indicate the additive effect of protons. Actually, a catalytic process is formed by protonation of the metal-oxygen bond instead of silylation. 2,6-Lutidine hydrochloride or 2,4,6-collidine hydrochloride serves as a proton source in the Cp2TiCl2-catalyzed pinacol coupling of aromatic aldehydes in the presence of Mn as the stoichiometric reduc-tant [30]. Considering the pKa values, pyridinium hydrochlorides are likely to be an appropriate proton source. Protonation of the titanium-bound oxygen atom permits regeneration of the active catalyst. High diastereoselectivity is attained by this fast protonation. Furthermore, pyridine derivatives can be recovered simply by acid-base extraction or distillation. 

MgS04, the tetracycles 2-648 were obtained with excellent diastereoselectivity in reasonable yield. The reaction presumably starts with a condensation of the aldehydes 2-645 with the benzyl-protected amine moiety of 2-644 to give an iminium ion which can subsequently cyclize to afford the spirocyclic intermediates 2-646. A [3,3] sigmatropic Cope rearrangement then forms the nine-membered cyclic enamines 2-647 which, after protonation, act as the starting point for another indole iminium cyclization to provide the tetracycles 2-648 via 2-647. 

Chiral tetrahydroisoquinoline derivatives can be obtained by diastereoselective or enatioselective protonation. Deprotonation of lactam 87 with n-BuLi followed by addition of H2O and NH4CI afforded 88 in 92% yield and 97% ee. The stereoselectivity was highly dependent upon the proton source. Further elaboration afforded tetrahydroisoquinoline 89 in >97% ee . The enantioselective protonation of 1-substituted tetrahydroisoquinoline 90 in the presence of chiral amine 91 proceeded in 90-95% yield and 83-86% ee. This methodology was used in an asymmetric synthesis of salsolidine <00SL1640>. 

Carbamate substituents have also been found to permit the direct removal of allylic, propargylic and allenic protons by organolithium reagents [32, 33]. In the latter case, the resulting lithioallenes can be converted to the allenyltitanium reagents with ClTi(OiPr)3 (Eq. 9.28) [8]. As illustrated, subsequent addition to acetaldehyde proceeds with only modest diastereoselectivity. 

The allenylindium intermediates are prepared by treatment of the aziridines with Pd(PPh3)4 in THF-HMPA containing 1 equivalent of water. In the presence of iso-butyraldehyde the expected adducts were formed with excellent diastereoselectivity (Tables 9.56 and 9.57). Interestingly, the reaction did not proceed in the absence of water. It is suggested that water is needed to protonate the sulfonamide anion of the initially formed allenyl palladium species (Eq. 9.150). 

It is also possible to oxidize allenes 89 and 92 to unsaturated hydroxy ketones 91 and 93 via the spirodioxide intermediate 90 [29]. In this case the terminating step is a 1,5-proton shift. In the examples shown in Scheme 17.26, the formation of the spirodioxide intermediate is diastereoselective, as is the rearrangement to the unsaturated hydroxy ketone. 

The cis/trans ratio of 1,4-disubstituted cyclohexanes formed from activated cyclohexenes at a Hg cathode depends on the solvent and proton source and shows a low diastereoselectivity. Protonation of the first formed radical anion is kinetically... 

Scheme 3.6. Diastereoselectivity in silylcuprate conjugate addition-alkylation (alkyl halides) or protonation reactions with a,/S-enoates [46],...

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